U.S. patent application number 10/108659 was filed with the patent office on 2003-07-24 for method of treatment.
Invention is credited to Gibson, Karen.
Application Number | 20030139396 10/108659 |
Document ID | / |
Family ID | 46280439 |
Filed Date | 2003-07-24 |
United States Patent
Application |
20030139396 |
Kind Code |
A1 |
Gibson, Karen |
July 24, 2003 |
METHOD OF TREATMENT
Abstract
There is described a method of treatment of a patient suffering
from constipation characterised in that the method comprises the
administration of a therapeutically effective amount of devazepide.
There is also described a method of treatment of a patient
requiring analgesia which comprises the separate, simultaneous or
sequential administration of a therapeutically effective amount of
an analgesic and a stool softening amount of devazepide. The use of
devazepide in the manufacture of a medicament is also
described.
Inventors: |
Gibson, Karen; (Sheffield,
GB) |
Correspondence
Address: |
ARTER & HADDEN, LLP
1100 HUNTINGTON BUILDING
925 EUCLID AVENUE
CLEVELAND
OH
44115-1475
US
|
Family ID: |
46280439 |
Appl. No.: |
10/108659 |
Filed: |
March 27, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10108659 |
Mar 27, 2002 |
|
|
|
10053962 |
Jan 22, 2002 |
|
|
|
Current U.S.
Class: |
514/221 |
Current CPC
Class: |
A61K 31/5513 20130101;
A61K 31/465 20130101; A61K 31/5513 20130101; A61K 2300/00 20130101;
A61K 31/465 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/221 |
International
Class: |
A61K 031/5513 |
Claims
1. A method of treatment of a patient suffering from constipation
characterised in that the method comprises the administration of a
therapeutically effective amount of devazepide.
2. A method of treatment according to claim 1 characterised in that
the constipation experienced is due to the administration of an
analgesic.
3. A method of treatment according to claim 2 characterised in that
the analgesic is an opioid analgesic.
4. A method of treatment according to claim 1 characterised in that
the method comprises the administration of an analgesic with a
stool softening amount of devazepide.
5. A method of treatment of a patient requiring analgesia which
comprises the separate, simultaneous or sequential administration
of a therapeutically effective amount of an analgesic and a stool
softening amount of devazepide.
6. A method of treatment according to any one of claims 1 or 5
characterised in that the amount of devazepide administered is
sufficient so that the devazepide exhibits a stool softening effect
and an analgesic potentiating effect.
7. A method of treatment according to claim 5 characterised in that
the analgesic is an opioid analgesic.
8. A method according to any one of claims 3 or 7 characterised in
that the opioid is selected from morphine, or a salt thereof such
as the sulphate, chloride or hydrochloride, or the other
1,4-hydroxymorphinan opioid analgesics such as meperidine,
butorphanol or pentazocine, or morphine-6-glucuronide, codeine,
dihydrocodeine, diamorphine, dextropropoxyphene, pethidine,
fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide,
diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocodone
(dihydrocodeinone), hydromorphone (dihydromorphinone), levorphanol,
meptazinol, methadone, metopon (methyldihydromorphinone),
nalbuphine, oxycodone (dihydrohydroxycodeinone- ), oxymorphone
(dihydrohydroxymorphinone), phenadoxone, phenazocine, remifentanil,
tramadol, or a salt of any of these.
9. A method according to any one of claims 3 or 7 characterised in
that the opioid is naloxone.
10. A method according to claim 8 characterised in that the
analgesic is selected from the group hydromorphone, oxycodone,
morphine, e.g. morphine sulphate and fentanyl.
11. A method according to claim 8 characterised in that the opioid
is fentanyl or a salt thereof.
12. A method according to claim 10 characterised in that the
analgesic is selected from the group morphine and morphine
sulphate.
13. A method according to any one of claims 1 or 5 characterised in
that the devazepide and/or the opioid may be administered using a
method selected from administration intravenously, orally,
intrathecally, intranasally, intrarectally,
intramuscularly/subcutaneously, by inhalation and by transdermal
patch.
14. A method according to claim 13 characterised in that the
devazepide and/or the opioid is administered intravenously.
15. A method according to claim 14 characterised in that the
intravenous administration is by intravenous bolus or a continuous
intravenous infusion.
16. A method according to claim 13 characterised in that the
devazepide and/or the opioid is administered subcutaneously.
17. A method according to claim 16 characterised in that the
subcutaneous administration is as a subcutaneous infusion.
18 A method according to claim 13 characterised in that the opioid
and/or devazepide are administered orally.
19. A method according to claim 13 characterised in that the opioid
and the devazepide are administered using the same mode of
administration.
20. A method according to claim 19 characterised in that the opioid
is administered orally and the devazepide is administered
orally.
21. A method according to claim 13 characterised in that the opioid
is administered by transdermal patch.
22. A method according to claim 21 characterised in that the opioid
is fentanyl, or a salt thereof.
23. A method according to any one of claims 1 or 5 characterised in
that the daily dosage of devazepide may be up to 0.7 mg/kg/day.
24. A method according to claim 23 characterised in that the daily
dosage of devazepide is from 25 .mu.g/kg/day to 0.7 mg/kg/day.
25. A method according to claim 24 characterised in that the daily
dosage of devazepide is from 50 .mu.g/kg/day to 0.5 mg/kg/day.
26. A method according to claim 23 characterised in that the dosage
of devazepide is an oral dosage.
27. A method according to claim 26 characterised in that for oral
administration the daily dosage of devazepide is from 0.07
mg/kg/day to 0.29 mg/kg/day.
28. A method according to claim 14 characterised in that for
intravenous administration the dosage of devazepide is 50
.mu.g/kg/day to 0.5 mg/kg/day.
29. A method according to claim 3 or 5 characterised in that the
dosage of the opioid is from 5 to 2000 mg daily.
30. The use of devazepide in the manufacture of medicament suitable
for use as a stool softener.
31. The use according to claim 30 characterised in that the
medicament is suitable for co-administration comprises the
separate, simultaneous or sequential administration with an opioid
analgesic.
32. The use according to claim 31 characterised in that the
medicament comprises a composition of devazepide and an opioid
analgesic.
33. The use according to claim 30 characterised in that the
devazepide is provided as a composition incorporating a filler or
other excipient.
34. The use according to claim 33 characterised in that the
composition is filled into a capsule.
35. The use according to claim 34 characterised in that the capsule
is gelatin capsule.
36. The use according to claim 34 characterised in that the
composition is made up into a capsule formulation with a fill
weight of 150 mg.+-.5% by weight or 300 mg.+-.5% by weight.
37. The use according to claim 34 characterised in the capsule
comprises 1.25 mg devazepide or 2.5 mg devazepide.
38. A method of treatment of a patient undergoing opioid analgesic
therapy which comprises the administration of a capsule formulation
comprising 1.25 mg devazepide or 2.5 mg devazepide.
39. A method according to claims 1 or 5 characterised in that the
devazepide used in the method of the invention is substantially the
S enantiomer.
40. A method according to claim 39 characterised in that the level
of R enantiomer, which may be present as an impurity, is not
greater than 1.5% w/w.
41. A composition or a method substantially as described with
reference to the accompanying examples.
Description
[0001] This invention relates to a novel method of treatment
related thereto and a novel use related thereto.
[0002] International Patent Application No. WO 99/18967 describes
pharmaceutical compositions for treating chronic and neuropathic
pain which comprises an analgesic amount of an opioid and an opioid
potentiating amount of a CCK antagonist. WO '967 describes the use
of both CCK-A antagonists and CCK-B antagonists, although it is
described that, generally, CCK-B antagonists are preferred.
Moreover, page 2, lines 6 to 8 of WO '967 describes that CCK-A
antagonists may be suitable, but only at relatively higher
dosages.
[0003] One specific CCK-A antagonist which is mentioned in WO
99/18967 is devazepide (Devacade.RTM.), which is
3s-(-)-1,3-dihydro-3-(2-indolecarbon-
ylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
[0004] Devazepide is commonly administered alongside an opioid
analgesic, e.g. such as morphine. However, in normal doses, among
the commonest side-effects of morphine and other opioid analgesics
are nausea, vomiting, constipation, drowsiness, and confusion;
tolerance generally develops with long-term use, but not to
constipation which is the most common undesirable side effect of
morphine treatment.
[0005] International Patent Application No. WO 99/18967
specifically describes a pharmaceutical formulation comprising a
CCK antagonist, such as devazepide, an opioid and a biphasic
carrier, comprising a glyceride derivative organic phase. This
application suggests the possible use of a surfactant, especially
when the formulation is in the form of an oil-in-water
emulsion.
[0006] We have now surprisingly found that devazepide may also
reduce or mitigate the undesirable side effects of opioid
administration, e.g., in particular, constipation.
[0007] Thus, according to the invention we provide a method of
treatment of a patient suffering from constipation characterised in
that the method comprises the administration of a therapeutically
effective amount of devazepide.
[0008] The method of the invention is especially suited to the
treatment of constipation experienced due to the administration of
an analgesic, such as an opioid analgesic.
[0009] Thus, according to the invention we especially provide a
method of treatment of a patient suffering from constipation
experienced due to the administration of an analgesic, such as an
opioid analgesic, characterised in that the method comprises the
administration of a therapeutically effective amount of
devazepide.
[0010] The method of the invention may comprise the administration
of an analgesic with devazepide, e.g. a stool softening amount of
devazepide.
[0011] Thus, according to this aspect of the invention we provide a
method of treatment of a patient requiring analgesia which
comprises the separate, simultaneous or sequential administration
of a therapeutically effective amount of an analgesic and a stool
softening amount of devazepide.
[0012] Most preferably the amount of devazepide administered is
sufficient so that the devazepide exhibits a stool softening effect
and an analgesic potentiating effect.
[0013] In the method of the invention the analgesic is preferably
an opioid. A variety of opioids may be used. Thus, the opioid may
be selected from those which are effective analgesics and
particularly those which need to be administered at relatively high
or increasing doses. Examples include morphine, or a salt thereof
such as the sulphate, chloride or hydrochloride, or the other
1,4-hydroxymorphinan opioid analgesics such as meperidine,
butorphanol or pentazocine, or morphine-6-glucuronide, codeine,
dihydrocodeine, diamorphine, dextropropoxyphene, pethidine,
fentanyl, alfentanil, alphaprodine, buprenorphine, dextromoramide,
diphenoxylate, dipipanone, heroin (diacetylmorphine), hydrocodone
(dihydrocodeinone), hydromorphone (dihydromorphinone), levorphanol,
meptazinol, methadone, metopon (methyldihydromorphinone),
nalbuphine, oxycodone (dihydrohydroxycodeinone- ), oxymorphone
(dihydrohydroxymorphinone), phenadoxone, phenazocine, remifentanil,
tramadol, or a salt of any of these. Naloxone is also included
within the definition of an opioid. Especially preferred analgesics
which may be mentioned are hydromorphone, oxycodone, morphine, e.g.
morphine sulphate and fentanyl. In a preferred embodiment of the
invention the analgesic is morphine or morphine sulphate. In a
further preferred embodiment the opioid is fentanyl, or a salt
thereof.
[0014] In the method of the invention the devazepide and/or the
opioid may be administered using any methods conventionally known
per se. Thus, such methods would include, but shall not be limited
to, administration intravenously, orally, intrathecally,
intranasally, intrarectally, intramuscularly/subcutaneously, by
inhalation and by transdermal patch. When the devazepide and/or
opioid is administered intravenously, it may, for example, be as an
intravenous bolus or a continuous intravenous infusion. When the
devazepide and/or the opioid is administered subcutaneously, it
may, for example, be by subcutaneous infusion. Preferably, the
opioid and/or devazepide are administered orally. Preferentially,
the opioid and the devazepide will be administered using the same
mode of administration. Thus, for example, when the opioid is
administered orally then the devazepide may be administered orally
also. However, it is within the scope of the invention for the
opioid to be administered intravenously and the devazepide to be
administered orally. In a further preferred embodiment the opioid
may be administered by a transdermal patch. When a transdermal
patch is used, the preferred opioid is fentanyl.
[0015] Thus, in the method of the invention the daily dosage of
devazepide may vary depending upon, inter alia, the weight of the
patient, the method of administration, etc. In patients that are
suffering serious disorders, such as cancer patients, the weight of
the patient may be very low and therefore the dosage of devazepide
consequentially may be low. Thus the daily dosage of devazepide may
be up to 0.7 mg/kg/day. Preferably, the daily dosage of devazepide
may be from 25 .mu.g/kg/day to 0.7 mg/kg/day, more preferably from
50 .mu.g/kg/day to 0.5 mg/kg/day. For oral administration the daily
dosage of devazepide may be from 0.07 mg/kg/day to 0.7 mg/kg/day,
preferably 0.07 mg/kg/day to 0.29 mg/kg/day. For intravenous
administration the dosage of devazepide is preferably 50
.mu.g/kg/day to 0.5 mg/kg/day.
[0016] In the method of the invention the dosage of the opioid
analgesic administered may vary depending upon, inter alia, the
nature of the opioid analgesic, the weight of the patient, the
method of administration, etc. Thus, for example, the dosage of,
e.g. an opioid, such as morphine, may be from 5 to 200 mg daily. A
particular dosage which may be mentioned is from 10 to 240 mg
daily. A daily dosage of morphine may be from 5 to 100 mg or
occasionally up to 500 mg.
[0017] In the method of the invention devazepide may be provided as
a composition incorporating, for example, a filler, or other
excipient.
[0018] Thus, for example, in one embodiment of the invention the
composition may be made up into a capsule formulation, e.g. with a
fill weight of 150 mg.+-.5% by weight or 300 mg.+-.5% by weight. In
the one preferred embodiment, the capsule formulation may comprise
1.25 mg devazepide, and 148.75 mg of a filler or other excipient,
e.g. corn starch. In a further preferred embodiment, the capsule
formulation may comprise 2.5 mg devazepide, and 297.5 mg of a
filler or other excipient, e.g. corn starch.
[0019] Thus, such fillers may be selected from the group lactose,
mannitol, talc, magnesium stearate, sodium chloride, potassium
chloride, citric acid, spray-dried lactose, hydrolysed starches,
directly compressible starch, microcrystalline cellulose,
cellulosics, sorbitol, sucrose, sucrose-based materials, calcium
sulphate, dibasic calcium phosphate and dextrose. A preferred
filler is starch, e.g. corn starch.
[0020] When the composition of the invention includes a filler, the
size of the devazepide and filler particles may be the same or
different. However, in a preferred embodiment the sizes of the
devazepide and filler particles will differ. Preferentially, the
devazepide and/or the filler may be of reduced particle size, e.g.
by milling.
[0021] A preferred embodiment of the invention comprises a
formulation as hereinbefore described filled into a capsule. Any
conventionally known materials may be used for the capsule, however
a preferred material is gelatin.
[0022] According to a further aspect of the invention we provide a
method of treatment of a patient undergoing opioid analgesic
therapy which comprises the administration of a pharmaceutical
composition as hereinbefore described.
[0023] According to a further aspect of the invention we provide
the use of devazepide in the manufacture of medicament suitable for
use in a method as hereinbefore described.
[0024] The devazepide used in the method of the invention is the S
enantiomer, preferentially, the S enantiomer wherein the level of R
enantiomer, which may be present as an impurity, is not greater
than 1.5% w/w.
* * * * *